J . Am. Chem. SOC.1982, 104, 6081-6091
608 1
Synthesis of Sesquiterpene Antitumor Lactones. 10. Total Synthesis of (&)-Parthenin’ Clayton H. Heathcock,* Colin M. Tice, and Ted C. Germroth Contribution from the Department of Chemistry, University of California, Berkeley, California 94720. Received March 8, 1982
- -
Abstract: (&)-Parthenin (1) has been prepared in 22 steps from cyclohexenone. The synthetic strategy employed involves annelation of the five-membered ring onto a preexisting cycloheptane precursor (5 21 3). Alkylation of the lithium enolate of cis-fused hydroazulenone 22 gives entirely the desired 70-oriented isomer 23. Base-catalyzed equilibration of 23 provides the 7a epimer 24. Conformational analysis of this equilibrium, using the Allinger M M 1 force field, suggests that a part of the reason for the predominance of 24 is the fact that it has two conformations that are of equal energy while 23 is restricted to a single conformation. Reduction of 23 by diisobutylaluminum hydride in ether gives isomers 30 and 31 in a ratio of 13:l. Compound 30 is converted into the keto lactone 2 by ozonolysis, deprotection, and oxidation. The complete stereostructure of compound 2 was established by single-crystal X-ray analysis. The cyclopentane ring is functionalized as shown in Scheme V. Ketalization of enone 42 affords unsaturated lactone 43, which is epoxidized by m-chloroperoxybenzoic acid to obtain epoxide 48. The a-methylene unit is introduced by the use of Stiles’ reagent, via carboxy lactone 52. The final step in the synthesis is acid-catalyzed hydrolysis of the ketal in 54, which leads directly to (*)-parthenin (1). The synthesis provides interesting information on the stereochemistry of cis-fused pseudoguaianolide precursors, a class of compounds not extensively investigated heretofore.
Scheme I I n t h e previous paper in this series’ we discussed four basic strategies for construction of the hydroazulene ring system characteristic of the pseudoguaianolides. In the eleven published synthetic approaches to these interesting sesquiterpenes, three of these strategies have been examined (Scheme I). In this paper, we report a n application of the fourth method, which involves fusion of the five-membered ring onto a preexisting cycloheptane ring, in a total synthesis of the interesting sesquiterpene parthenin ( l ) , the substance largely responsible for the allergic contact dermatitis caused by the bitter herb Parthenium h y s t e r o p h o r u ~ . ~ ~ ~ Scheme I1 T h e synthetic strategy is summarized in Scheme 11. T h e proposed cyclopentane annelation (4 or 5 3) was to be carried out along the lines previously developed in this laboratory and was expected to afford a cis-fused hydroazulenone having the correct relative stereostructure a t the two methyl centers (future C5 and C10).4 Although this strategy must proceed through intermediates having the unnatural configuration a t C,,5 this is I of no consequence in a synthesis of parthenin, since this position must eventually be oxidized. I n addition, t h e approach summarized in Scheme I1 offered an opportunity to evaluate the efficacy of cis-fused hydroazulenones for establishing the desired sense of chirality a t c6 and C7. As will be seen, the approach offers certain advantages in this regard. T h e required cycloheptenones were prepared a s summarized in Scheme IIL6 As previously described5 4-methylcyclohept-2Scheme I11 en-1-one (4) is obtained in 54% overall yield from cyclohexenone by t h e method of I t o a n d S a e g ~ s a . Enone ~ 4 was employed in the developmental stages of the synthesis. Recently Conia and co-workers reported a convenient synthesis of 2,4-dimethylcyclohept-2-en- 1-one (5,70% overall from cyclohexenone)* that
0
0
al
-
(1) For part 9, see: C. H. Heathcock, E. G. DelMar, and S . L. Graham, J . Am. Chem. SOC.,104, 1907 (1982). (2) (a) H. V. Arny,J. Pharm., 121 (1850); 169 (1897). (b) W. Herz, and H. Watanabe, J . Am. Chem. SOC.,81, 6088 (1959). (c) W. Herz, H. Watanabe, M. Miyazaki, and Y . Kishida, ibid., 84, 2601 (1962). (d) M. T. Emerson, C. N. Caughlan, and W. Herz, Tetrahedron Lett., 6151 (1566). (e) E. Rodriguez, G. H. N. Towers, and J. C. Mitchell, Phytochemistry, 15, 1573 (1976).
(3) For a previous total synthesis of parthenin, see: P. Kok, P. De Clercq, and M. Vandewalle, Bull. SOC.Chim. Eelg., 87, 615 (1978). (4) D. N. Brattesani and C. H . Heathcock, J . Org. Chem., 40, 2165 ( 1975).
(5) C. H. Heathcock, T. C. Germroth, and S. L. Graham, ibid., 44, 4482 (1979). (6) Although only one enantiomer is depicted in each case, all compounds
in this paper are racemates. (7) Y. Ito, S. Fujii, and T. Saegusa, J . Org. Chem., 41, 2073 (1576). (8) (a) L. Blanco, N. Slougi, G. Rousseau, and J. M. Conia, Tetrahedron Lett., 22,645 (1981). (b) L. Blanco, P. Amice, and J. M. Conia, Synthesis, 289 (1981).
0002-7863/82/1504-6081$01.25/0
3
2
4 R=H 5 R = CH3
a q)
Me3Si0
(64%)
Q
7
4
&
c
Me3Si0
8
5 a d
M e p C u L i , M e 3 S i C I , E f 3 N , b CH212. Z n ( C u ) , c FeC13, p y r i d i n e . DMF, NaOAc, MeOH, e CH3CHC12, n-BuLI, E f 2 0 , -2O’C, f Et3N, MeOH, A
was used in the final version of our work. Previous studies had shown that cycloheptenone 4 reacts with organocuprate reagents to give predominantly trans-3,4-dia l k y l c y ~ l o h e p t a n o n e s .Thus, ~ treatment of 4 with the Grignard reagent prepared from bromo acetal 94 in the presence of cuprous iodide affords a 4:l mixture of ketones 10 in 57% yield. Acidcatalyzed hydrolysis of the acetal is accompanied by aldolization
0 1982 American Chemical Society
J . Am. Chem. Soc., Vol. 104, No. 22, 1982
6082
Heathcock, Tice, a n d Cermroth
Table I. Hydrolysis-Aldolization of Keto Acetal 13
H
Me
product distribution
en- sol- temp, try venta "C
1 2 3 4 5 6 7
A A A B B B B
yield, time, h
14
3
15
other
20 22 55 2.5 48 0.4 1
60 0 0 61 0 0 0
0 57 42 32 100 100 70
0 43 58 0 0 0 30
40'
30 reflux reflux 30 30 reflux reflux
%b
-~
0 60 0 62 7d 0 64 0 50 0 60 a Solvent A = 5 :1 mixture of EtOH and 10% aqueous HC1; solvent B = 5 : l mixture of HOAc and 10%aqueous HCI. &I Yield of isolated, purified mixture of 3 and 15. Diethyl acetal of keto aldehyde 14. Keto acetal 13.
la1
I bl
Figure 1. Transition states leading from keto aldehyde 14 to trans- and cis-hydroazulenes. show that acetal hydrolysis is more rapid than aldolization (entries 1 and 4). It also establishes that isomer 3 is the kinetic product of aldolization and that isomer 15 results from subsequent equilibration (entires 2 and 3, 6 and 7), presumably via keto aldehyde 14. That 3 and 15 are isomeric a t the secondary alcohol position was shown by the fact that they give the same dione (16)
and dehydration, providing a similar 4: 1 ratio of hydroazulenones 11. As shown by subsequent transformation, the major isomer
18
a
I1
10
9 Mg, THF, enone 4. C U I ;
b . 5 % H C I , EtOH, reflux, I hr
of 11 is the one having the methyl group a t C, and the hydrogen a t C3acis. Attempts to methylate 11 a t Cgawith methyl iodide and various bases ( N a H , Me2SO; t-BuOK, r-BuOH; K H , T H F ) failed to give useful amounts of methylated products. W e were also unable to methylate the magnesium enolate resulting from conjugate addition to enone 4. However, silylation of the conjugate addition product provides an enol ether (12),which may be treated
I
OSiMe3
12 0
Mg, THF, C U I , enone 4 , Me3SiCI, EtSN
I3 b MeLi, DME, M e I , 5'C
with methyllithium in 1,2-dimethoxyethane ( D M E ) to form the corresponding lithium enolate. Methylation of this species affords ketone 13 in an overall yield of 56%.9 Although 13 is produced a s a diastereomeric mixture, the methylation actually occurs with considerable stereoselectivity. T h e two C2 epimers (each a 4:l epimeric mixture a t C,) a r e produced in a ratio of 9:1 (I3C N M R spectroscopy, H P L C , isolation). When keto acetal 13 is treated with HC1 in aqueous ethanol or aqueous acetic acid the acetal group is hydrolyzed a n d the resulting keto aldehyde 14 cyclizes to a mixture of hydroxy ketones
14
3
IS
3 and 15.1° T h e ratio of 3:15 is found to be dependent on the conditions under which the hydrolysis-cyclization is carried out. Results a r e shown in Table I. (When aqueous acetic acid is employed, there is some acetylation of the initial hydroxy ketone products. In this case, acid treatment is followed by saponification with methanolic sodium methoxide.) The data in the table clearly (9) The procedure is that of Coates and Sandefur (R. M. Coates and L. 0. Sandefur, J . Org. Chem., 39, 275 (1974)). (10) Compounds 3 and 15 are each produced as a 4:l mixture of epimers at C8, of which only the major isomer is depicted in each case.
upon oxidation. The cis fusion of the two rings was assigned on the basis of examination of molecular models, which show that there is more torsional strain involved in bringing the propionaldehyde chain from one side of the cycloheptane ring to the other (Figure l a ) than in the analogous transition state leading to the cis-fused product (Figure l b ) . This hypothesis was verified by single-crystal X-ray analysis of a subsequent conversion product of 3. T h e relative configurations of the C3 hydroxy groups in 3 a n d 15 a r e assigned on the basis of the infrared spectra of the two hydroxy ketones. In the kinetic product, the OH stretch appears as a sharp absorption a t 3595 cm-I a t 2% concentration in CC14 and as a broad band a t 3500 cm-' a t 10% concentration. For the thermodynamic product the OH stretch is a broad band a t 3550 cm-I a t all concentrations. Drieding stereomodels of 3 and 15 indicate that the latter is capable of intramolecular H bonding while the former is not. It is interesting to speculate why equilibration of 3 and 15 does not lead to a trans-fused aldol, since trans-hydroazulenes are usually more stable t h a n their cis isomers.l*11,'2 A similar equilibration (17 18) has been observed by Vandewalle and
17
18
IS
20
co-workers.I3 In this case, only cis-fused aldols are detected, even though the closely related dione 19 yields principally the transfused isomer 20 upon equilibration.I2 This behavior is consistent with a hypothesis that there is a substantial difference in the energies of the two transition states depicted in Figure 1, such that there is a n effective kinetic barrier to formation of the trans-fused isomers by intramolecular aldolization. Although the annelation sequence leading from cycloheptane 4 to hydroazulene 3 is reasonably brief, it proceeds in an overall yield of only 36% a t best and is often unreliable in large-scale application. S o m e of the loss in yield is obviously incurred in the process of introducing the C, methyl group, which requires three separate operations. For this reason, the use of enone 5 is par(11) J. A. Marshall, Synthesis, 517 (1972). (12) P.De Clercq and M. Vandewalle, J . Org. Chem., 42,3447 (1977). (13) M. Vandewalle, private communication.
J . Am. Chem. SOC.,Vol. 104, No. 22, 1982 6083
Total Synthesis of (*)-Parthenin
nn
ticularly appealing. However, attempts to bring about conjugate addition of the Grignard reagent derived from halide 9 to enone 5 failed; only recovered starting material and its 1,2-addition product were obtained. Similar results were obtained with 3butenyl- 1-magnesium bromide. The reluctance of enones bearing alkyl substituents a t C, or C3 to react with cuprate reagents is well p r e ~ e n d e n t e d . ' ~A solution to this dilemma is found in the use of Yamamoto's reagent.I5 Thus, the complex formed by adding first 1 equiv of cuprous iodide and then 1 equiv of boron trifluoride etherate to 3-butenyl-1-magnesium bromide adds smoothly to enone 5 to give adduct 21 as a diastereomeric mixture
21 a
CH2=CHCH2CH2Cu*BF3,
Me2S.
c
T H F , -78'C,
b 03, MeOH, CH2C12, - 7 8 T ,
H C I , H20. H O A c , 3 0 " C , 52 h r . NaOMe, MeOH. 3 0 T . I hr
in 59% yield. Unfortunately, the Grignard reagent obtained from halide 9 is not effective in this reaction.I6 Ozonolysis of 21 in methanolic methylene chloride, followed by dimethyl sulfide workup, gives a mixtue of keto aldehyde 14 and its dimethyl acetal. When this mixture is stirred a t room temperature with H C l in aqueous acetic acid for 52 h (cf. Table I, entry 5) hydroazulene 3 is formed in 75% overall yield. T h e modified synthesis via cycloheptenone 5 provides 3 in six steps and 31% overall yield from cyclohexenone as compared to eight steps and 19% overall yield for the synthesis via cycloheptenone 4. In addition, the Yamamoto procedure for conjugate addition is more stereoselective ( 5 : 1 vs. 4:1), presumably because it is carried out a t -78 " C rather than a t -20 OC. With a reliable synthesis of 3 in hand, it was next necessary to introduce a suitable alkyl group and fashion the y-butyrolactone ring with the desired relative configuration a t the eventual C6 and C7 positions. For investigation of this operation without the possible complication of reverse aldolization, the secondary alcohol was protected as the methoxymethyl ether (22). A t this point the C 8 epimers are easily separated by chromatography; the remaining operations are carried out with pure 22. Alkylation of the lithium enolate of ketone 22 with allyl bromide gives a single
22
23
24
Figure 2. Perspective drawings of minimum energy conformations of hydroazulenes 28 and 29. (A) 29, twist-boat, (B) 29, twist-chair, (C) 28, twist-boat, (D) 28, twist-chair. The highly stereoselective alkylation of ketone 22 is explicable in terms of steric hindrance to approach to the cy face of the enolate
22a: Ma
22a
The hypothesis that chelation of the lithium cation by the (?-oxygen of the methoxymethyl group is important is based on a study of the alkylation of the related keto ether 25 with prenyl bromide; isomers 26 and 27 are produced in a ratio of 3:1.18
27
26
21
House and co-workers have shown that the Allinger M M l force fieldlg successfully reproduces strain energies in cycloheptane derivatives.*O Therefore, we evaluated the equilibrium 23 + 24 in this manner. To facilitate the analysis, we calculated strain energies for various conformations of the model keto alcohols 28 and 29. For compound 29, two low-energy conformations, one
a . CH30CH2CI, ( / - P r I 2 E t N , CH2C12. b chromatographic s e p a r a t i o n O f Ce e p i m e r s , c L D A , D M E , CH2=CHCH2Br, 3 0 ° C . 3 h r s d NaOCH3. CH30H, r e f l u x , 12 h r s
product (23) in 85% yield. Analysis of this alkylation product by 13C NMR spectroscopy, TLC, and analytical H P L C established its homogeneity. T h e indicated stereostructure was elucidated by single-crystal X-ray analysis of a conversion product. Basecatalyzed equilibration of 23 provides a 1:9 mixture of 23 and its isomer 24.
(14) (a) G. H. Posner, Org. React. (N.Y), 19, 1 (1972). (b) H. 0. House, Acc. Chem. Res., 9, 59 (1976). (15) Y. Yamamoto and K. Maruyama, J . Am. Chem. SOC.,100, 3240 (1978). (16) The failure of this reaction is apparently due to the failure of the Grignard reagent to form a stoichiometric cuprate upon addition of the CUI. When a Grignard solution is treated with CUI, formation of the cuprate is normally evidenced by the production of a black suspension. In this case the solution remains pale yellow. (17) A similar increase in stereoselectivity under the Yamamoto conditions is seen in addition of methylcopper, n-propylcopper, and 3-butenylcopper to enone 4.18
28
29
a twist-boat (Figure 2A) and the other a twist-chair (Figure 2B), were found. The calculated strain energies for these two conformations are 14.7 and 14.8 kcal mol-', respectively. For isomer 28 there is only one low-energy conformation, a twist-boat (Figure 2C), with a calculated strain energy of 14.6 kcal mol-'. The twist-chair conformation of 28 is destabilized by a serious methyl-methyl interaction (Figure 2D) and has a calculated strain energy of 16.3 kcal mol-'. Although the force-field calculations do not predict an enthalpy difference between isomers 28 and 29, they do predict that isomer 29 will be favored over isomer 28 for entropic reasons. (18) For full details, see C. M. Tice, Ph.D. Thesis, University of California, Berkeley, 1981. (19) N. L. Allinger and D. H. Wertz, Tetrahedron, 30, 1579 (1974), and previous papers cited in this reference. (20) H. 0. House, C. C. Yau, and D. VanDerveer, J. Org. Chem., 44,3031 (1979).
6084
J . Am. Chem. Soc., Vol. 104, No. 22, 1982
Figure 3.
ORTEP
Heathcock, Tice, and Germroth
stereoplot of keto lactone 2.
Table 11. Reduction of Ketone 23=
Scheme IV
reducing agent
solvent
30:31
yield, %
LiAM, LiAl(OMe),H (iC4H, ) AlH (i-C,H,),AIHb (i-C4H,),AMb (~-c,H,),A~H~
ether ether hexane ether THF DME
42:58 50:50 72:28 93:7 71:29 89:ll
89 92 88 92 78' 89
35
34
a All reductions were carried out at -78 "C. The reagent is used as a 1.0 M solution in hexane. In this case 20% of starting material is also obtained.
T o complete the stereoselective elaboration of the cis-fused y-butyrolactone ring, it is necessary to reduce the carbonyl group of 23 from the face opposite the methyl and allyl appendages. T o evaluate the probability of success, we applied Wipke's steric congestion analysis2] to the twist-boat conformation of compound 28 (Figure 2C). T h e computation predicts that the top face of the carbonyl is more hindered than the bottom. On a quantitative basis, the relative steric hindrance ratio is found to be 96:4. Compound 23 was treated with a variety of hydride reducing agents to obtain alcohols 30 a n d 31. T h e results of a series of
31
30
reductions a r e summarized in Table 11. T h e d a t a show that stereoselectivity increases a s the effective bulk of the reducing reagent increases (LiAlH., < LiA1(OMe)3H < (i-C4H&A1H in hexane < (i-C4H9)2A1Hin ethereal solvents). In addition, the major isomer is that predicted by the steric congestion analysis. Ozonolysis of unsaturated alcohol 30 in methanol, followed by
37
36
Oihydropyran, p-TsOH, CH2C12 b L O A , T H F . lCH3)2C=CHCH28r H C I , H 2 0 , T H F , diaxone, 25'C, 16 h r d ( i - C q H g ) , A I H , ether, -IOO°C e 0 3 , MeOH. CHZCI2, Me$ f H C I , H,O, T H F , 25'C
a
c
The five-step conversion of hydroxy ketone 3 into keto lactone 2 establishes a viable method for constructing the y-butyrolactone ring with the desired configuration a t the two new asymmetric centers. However, it leaves something to be desired in terms of overall yield, particularly in large-scale runs. T h e problems lie with the deprotection and oxidation steps (32 2). Although both of these operations can be achieved in about 90% yield on small scale (
